title: Repeated cocaine weakens GABA(B)-Girk signaling in layer 5/6 pyramidal neurons in the prelimbic cortex.
abstract: Repeated cocaine exposure triggers adaptations in layer 5/6 glutamatergic neurons in the medial prefrontal cortex (mPFC) that promote behavioral sensitization and drug-seeking behavior. While suppression of metabotropic inhibitory signaling has been implicated in these behaviors, underlying mechanisms are unknown. Here, we show that Girk/K(IR)3 channels mediate most of the GABA(B) receptor (GABA(B)R)-dependent inhibition of layer 5/6 pyramidal neurons in the mPFC and that repeated cocaine suppresses this pathway. This adaptation was selective for GABA(B)R-dependent Girk signaling in layer 5/6 pyramidal neurons of the prelimbic cortex (PrLC) and involved a D₁/₅ dopamine receptor- and phosphorylation-dependent internalization of GABA(B)R and Girk channels. Persistent suppression of Girk signaling in layer 5/6 of the dorsal mPFC enhanced cocaine-induced locomotor activity and occluded behavioral sensitization. Thus, the cocaine-induced suppression of GABA(B)R-Girk signaling in layer 5/6 pyramidal neurons of the prelimbic cortex appears to represent an early adaptation critical for promoting addiction-related behavior.
authors.affiliation: Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Hearing
authors.forename: Lydia
authors.initials: L
authors.lastname: Kotecki
authors.forename: Ezequiel
authors.initials: E
authors.lastname: Marron Fernandez de Velasco
authors.forename: Ana
authors.initials: A
authors.lastname: Fajardo-Serrano
authors.forename: Hee Jung
authors.initials: HJ
authors.lastname: Chung
authors.forename: Rafael
authors.initials: R
authors.lastname: Luján
authors.forename: Kevin
authors.initials: K
authors.lastname: Wickman
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D003042:Cocaine / Q000494:pharmacology*; D058999:Drug-Seeking Behavior / Q000502:physiology; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D017447:Receptors, Dopamine D1; D005680:gamma-Aminobutyric Acid; D003042:Cocaine